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    Tumor Immunology BMS 3.1

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    Kato Caleb
    This document provides an overview of tumor immunology. It discusses basic concepts like cancer etiology, types of cancer, tumor antigens, and evidence of tumor immunity. It also summarizes key mechanisms of tumor recognition by the immune system including antibodies, cytokines, and antigen presentation. Finally, it describes ways tumors can be killed by both non-specific and antigen-specific immune cells as well as how tumors can activate or suppress the immune response.

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    Tumor Immunology BMS 3.1

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    Kato Caleb
    32 views38 pages
    This document provides an overview of tumor immunology. It discusses basic concepts like cancer etiology, types of cancer, tumor antigens, and evidence of tumor immunity. It also summarizes key mechanisms of tumor recognition by the immune system including antibodies, cytokines, and antigen presentation. Finally, it describes ways tumors can be killed by both non-specific and antigen-specific immune cells as well as how tumors can activate or suppress the immune response.

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    This document provides an overview of tumor immunology. It discusses basic concepts like cancer etiology, types of cancer, tumor antigens, and evidence of tumor immunity. It also summarizes key mechanisms of tumor recognition by the immune system including antibodies, cytokines, and antigen presentation. Finally, it describes ways tumors can be killed by both non-specific and antigen-specific immune cells as well as how tumors can activate or suppress the immune response.

    Copyright:

    © All Rights Reserved
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    32 views38 pages

    Tumor Immunology BMS 3.1

    Uploaded by

    Kato Caleb
    This document provides an overview of tumor immunology. It discusses basic concepts like cancer etiology, types of cancer, tumor antigens, and evidence of tumor immunity. It also summarizes key mechanisms of tumor recognition by the immune system including antibodies, cytokines, and antigen presentation. Finally, it describes ways tumors can be killed by both non-specific and antigen-specific immune cells as well as how tumors can activate or suppress the immune response.

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    © All Rights Reserved
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    of 38

    KAMPALA INTERNATIONAL UNIVERSITY

    FACULTY OF BIOMEDICAL SCIENCES


    DEPARTMENT OF MICROBIOLOGY &
    IMMUNOLOGY

    IMMUNOPATHOLOGY

    BMS 3.1

    TUMOR IMMUNOLOGY

    Course instructor: Reuben Maghembe (PhD)


    Email: [email protected],
    Mobile phone: +256741991783
    Learning Objectives
     Basics of and etiology of cancer
     Tumor immunorecognition
     Cancer cellular evasion mechanisms
     Cancer therapeutics
    Basic knowledge of cancer

     Defining a cancer, a turmor


     Molecular and biochemical aspects
     Pathological and immunological aspects
     Oncogenesis, carcinogenesis. tumorigenesis
     Forms, types of cancer
     Therapeutics
    FUNDAMENTAL QUESTIONS ON
    TUMOR IMMUNOLOGY

     What are cancer PAMPs?

     How does the immune system handle the cancer cell?


     Molecular mechanisms

     Is it effective? Why cancer then?

     Can we augment the immune system?


    Tumor
     Cells that proliferate and fail
    to differentiate into specialized
    normal but immortal cells
    1. Malignant: A tumor that grows
    indefinitely and spreads
    (metastasis)--also called
    cancer: kills host
    2. Benign: A tumor that is not
    capable of metastasis: does not
    kill host
    muscle, nerve, bone,
    blood
    Types of Cancer
     Carcinoma: arising from epithelial tissue, such as glands, breast,
    skin, and linings of the urogenital, digestive, and respiratory
    systems (89.3% of all cancers)
     Sarcoma: solid tumors of muscles, bone, and cartilage that arise
    from the embryological mesoderm (1.9% of all cancers)
     Leukemia: disease of bone marrow causing excessive production
    of leukocytes (3.4% of all cancers)
     Lymphoma, Myeloma: diseases of the lymph nodes and spleen
    that cause excessive production of lymphocytes (5.4% of
    cancers)
    The etiology of cancer
    1. Genetic factors: mutations,
    translocation, amplifications
    2. Environmental factors: UV,
    chemicals, viral infections

     conversion of proto-oncogenes (potential for cell transformation) to


    oncogenes (cell transformation)
     alteration in tumor suppressor genes
    Oncogenesis

    carcinogen
    results in mutation increased GF

    increased GF receptors
    proto-oncogenes oncogenes
    exaggerated response to GF

    tumor loss of ability to


    dysfunctional
    suppressor repair damaged
    tumor suppressor
    genes cells or induce
    genes
    inherited apoptosis
    defect
    Cancer cells are different

     Escape normal intercellular communication


     Allow for rapid growth
     Increased mobility of cells
     Invade tissues
     Metastasis
     Evade the immune system
    Evidence for Tumor Immunity
     Spontaneous regression: melanoma, lymphoma
     Regression of metastases after removal of primary tumor: pulmonary metastases
    from renal carcinoma
     Infiltration of tumors by lymphocytes and macrophages: melanoma and breast
    cancer
     Lymphocyte proliferation in draining lymph nodes
     Higher incidence of cancer after immunosuppression, immunodeficiency (AIDS,
    neonates), aging, (young&Adult) ,etc.
    Tumor Specific Antigens
    1) Mutated tumor cell proteins

    2) Tumor-specific mutated oncogenes or tumor suppressor genes

    3) Over-expression of normal antigens

    4) Viral oncogene expression on surface of the cell


    TUMOR OVEREXPRESSION OF
    NORMAL AG
    Tumor Associated Antigens
     Human Chorionic Gonadotropin (HCG)

     Alpha Fetoprotein (AFP)

     Prostate Specific Antigen (PSA)

     Mucin CA 125 (glycoprotein molecules on both


    normal epithelium and carcinomas)

     Carcinoembryonic Antigen (CEA)


    Tumor immunology

    Cancer immunosurveillance:
    immune system can recognize and destroy nascent transformed cells –
    -host protection process that inhibits carcinogenesis and maintains
    regular cellular homeostasis

    Cancer immunoediting:
    immune system kill and also induce changes in the tumor resulting in
    tumor escape –blocks tumor immunogenecity
    Antibody
     Direct attack: blocking growth factor receptors, arresting
    proliferation of tumor cells, or inducing apoptosis.
    -- is not sufficient to completely protect the body.
     Indirect attack: -- major protective efforts
    (1) ADCC (antibody-dependent cell mediated cytotoxicity )
    -- recruiting cells that have cytotoxicity, such as monocytes and
    macrophages.
    (2) CDC (complement dependent cytotoxicity)
    -- binding to receptor,initiating the complement system,
    'complement cascade’, resulting in a membrane attack
    complex, causing cell lysis and death.
    Cytokines
     Regulating the innate immune system: NK cells,
    macrophages, and neutrophils; and the adaptive immune
    system: T and B cells
     IFN- -- upregulating MHC class I, tumor antigens, and
    adhesion molecules; promoting activity of B and T cells,
    macrophages, and dendritic cells.
     IL-2 -- T cell growth factor that binds to a specific tripartite
    receptor on T cells.
     IL-12 – promoting NK and T cell activity, and a growth
    factor for B cells
     GM-CSF (Granulocyte-monocyte colony stimulating factor)
    --reconstituting antigen-presenting cells.
    Cancer immunotherapy
     Manipulation of co-stimulatory signal
     Enhancement of APC activities

     Cytokines
     IL-12 (promotes devt of Th-1 cells) , GM-CSF ( stimulates
    growth of macrophages and granulocytes), IL-1( activates local
    tissue destruction, increase access of T- effector cells,
    Endogenous pyrogen) IL-2 (stimulates helper and cytotoxic cells
    to grow, Is a T-cell growth factor), IL-5 (B- cell Differentiation
    factor, Enhances synthesis of Ig A, Stimulates production and
    synthesis of Eosinophils)
     Interferons
     IFN-γ ( activates phagocytic activities of macrophages, NK cells
    & neutrophils also increases synthesis of MHC 1 & 2), IFN-α,
    IFN-β ( block virus replication).
     Tumor necrosis factors
     TNF- α, TNF- β, exhibit direct antitumor, reduce proliferation
    and kill tumor cells, reduce angiogenesis
    Advantages of Immunotherapy for
    cancer

     Tumors are immunogenic


     Single cell kill
     Migrate to tissue
     Memory
     Specific
     Life-long protection
    Monoclonal antibodies
     these antibodies can be used to track down and reveal hidden cancer
    metastases within the body
     Biological response modifiers. are interferons (now obtained through
    genetic engineering) and interleukins.
     Monoclonal antibodies are used, for instance, to distinguish subsets of B
    cells and T cells.
     Immunotoxins

    Diphtheria toxin
    Immune Recognition of Tumor
    Antibodies recognize intact antigens while T cells
    recognize processed antigens associated with MHC
    Cross Presentation of
    Tumor Antigens
    Activation of naïve T cells Effector T cells: killers

    Signal I
    T cells

    Tumor

    Signal II
    Tumor killing

    Non-specific: NK cells,  T cells ,


    macrophages, NK T cells

    Antigen-specific: Antibody (ADCC,


    opsonization); T cells (cytokines,
    perforin/granzyme)
    Non-specific Tumor Killing
    NK T cells

    MIC A, B
    NKG2D
    Tumor NKT

    IFN-
    apoptosis Perforin/granzyme B
    Fas-L/Fas
    Antigen-specific tumor killing:
    B cells (opsonization & ADCC)

    Tumor

    sIg

    Macrophage/
    Complement opsinization

    Tumor

    Fc Fab FcR
    NK cells &
    ADCC
    Antigen-specific tumor killing:
    B Cells (blocking)

    T cell leukemia

    IL-2R Anti-IL-2R Ab
    IL-2
    Antigen-specific Tumor Killing:
    T Cells
    T cell receptor (TCR)

    MHCI
    CD8 Tumor

    peptide
    IFN-
    Granzyme B

    Apoptosis
    Tumors can both activate and suppress immunity

    Tumors can activate the immune response (ex. expression of foreign antigen
    with MHCI) or suppress the immune response (activation of T regulatory cells
    that release IL-10 and TGF) – the balance determines whether the cancer
    becomes clinically relevant or not
    Khong, H. T. et al. Nature Immunology 3, 999 - 1005 (2002)
    Basic Tumor Immunosurveillance

    1) The presence of tumor


    cells and tumor antigens
    initiates the release of
    “danger” cytokines such
    as IFN and heat shock
    proteins (HSP).
    2) These cause the
    activation and maturation
    of dendritic cells such
    that the present tumor
    antigens to CD8 and CD4
    cells
    3) subsequent T cytotoxic
    destruction of the tumor
    cells the occurs

    Smyth, M. J. et al. Nature Immunology 2, 293 - 299 (2001)


    Immunoediting of cancer cells

    Elimination refers to Equilibrium Escape refers to the


    effective immune refers to the rapid proliferation of
    surveillance selection for resistant clones in the
    resistant immunocompetent
    clones (red) host
    ELIMINATION PHASE

     Elimination: Phase 1-initiation of antitumor immune


    response(Innate)
     Due to local tissue damage led to the induction of
    inflammatory signals to the tumor site
     the infiltrating lymphocytes such as the natural killer cells
    and natural killer T cells are stimulated to produce IFN-
    gamma.
    ELIMINATION PHASE 2
     In phase 2 IFN-gamma induces tumor death AND promoting the
    production of chemokines-block blood vessels, why?
     Tumor cell debris produced taken by dendritic cells to the lymph
    nodes
     In phase 3, NKcells andmacrophages transactivate one another via the
    reciprocal production of IFN-gamma and IL-12. This again promotes
    more tumor killing by these cells via apoptosis
    Elimination: Phase 4

     In the final phase of elimination, tumor-specific CD4+ and


    CD8+ T cells home to the tumor site and the cytolytic T
    lymphocytes then destroy the antigen-bearing tumor cells
    which remain at the site.
    TUMOR ESCAPE MECHANISMS

    Or T regulatory cells

    Or kill them

    T regulatory cells
    Tumors can escape immunity (and immunotherapy) by
    selecting for resistant clones that have occurred due to
    genetic instability
    Avoidance of tumor surveillance through
    release of immune suppressants

    1 2

    1) Tumor cell production of immune suppressants such as


    TGF-,
    2) T regulatory cell stimulation with production of
    immune suppressants such as TGF- 
    Antitumor
    immune
    response

    1) Tumour-specific CD8+ T cells activated by dendritic cells (DCs) presenting tumour


    antigens can kill tumour cells directly. Both CD8+ and, especially, CD4+ T cells secrete
    IFN- , which can further sensitize tumour cells to CD8+ T cells by upregulating major
    histocompatibility complex (MHC) class I and other components of the antigen-
    processing machinery, promoting the recruitment of natural killer (NK) cells,
    granulocytes or macrophages, and interfering with crucial functions of the tumour
    stroma — namely, angiogenesis.
    2) Tumours can also be controlled by TH2-type immune responses, whereby DCs activate
    interleukin-5-secreting TH2 CD4+ T cells, which induce the accumulation of eosinophils
    in the tumour bed and/or provide 'T help' for the generation of a humoral, antibody-based
    antitumour response. Which pathway predominates depends on the biology of the
    tumour and/or the method of immunization.
    Gilboa E. Nature Reviews. Cancer. 4(5):401-11, 2004
    Tumor cells induce apoptosis in T
    lymphocytes via FAS activation

    1) Cancer cells express FAS


    ligand
    2) Bind to FAS receptor on T
    lymphocytes leading to
    apoptosis

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